Digital Commons Network^™

Frazzled And Abelson Interact To Regulate The Actin Cytoskeleton In Drosophila, Bridget Elsa Varughese

Wayne State University Dissertations

Guidance receptors such as Frazzled affect cell shape and motility by directly or indirectly modulating the cytoskeleton. Fra is particularly needed for the formation of the posterior commissures in a developing Drosophila embryo. The cytoplasmic tyrosine kinase, Abelson Kinase (Abl) enhances the loss of commissures observed in fra mutant. Abl physically interacts with Frazzled to help guide commissural axons across the midline. Furthermore, the loss of commissural axons is only seen when the actin dynamics are perturbed. Abl is also known to regulate actin-dependent processes underlying formation of filopodia, microspikes and membrane ruffles. So, we established a Drosophila S2 cell …

Axogial Communication Mediated By Soluble Neuregulin-1 And Bdnf, Zhenzhong Ma

Wayne State University Dissertations

During peripheral nervous system development, successful communication between axons and glial cells including Schwann cells in peripheral nervous system and oligodendrocytes in central nervous system, is required for the proper functions of both neurons and glia. Three types of alternatively-spliced proteins belonging to the neuregulin1 (NRG1) gene family of growth and differentiation factors are essential for Schwann cell survival and peripheral nerve development. While membrane-bound NRG1 forms (type III) has been strongly implicated in the regulation of myelination process at late stage of Schwann cell development, little is known about the role of soluble, heparin-binding forms of NRG1 (type I/II) …

Processing Random Signals In Neuroscience, Electrical Engineering And Operations Research, Kalyan Raman

Wayne State University Dissertations

The topic of this dissertation is the study of noise in electrical engineering, neuroscience, biomedical engineering, and operations research through mathematical models that describe, explain, predict and control dynamic phenomena. Noise is modeled through Brownian Motion and the research problems are mathematically addressed by different versions of a generalized Langevin equation. Our mathematical models utilize stochastic differential equations (SDEs) and stochastic optimal control, both of which were born in the soil of electrical engineering. Central to this dissertation is a brain-physics based model of cerebrospinal fluid (CSF) dynamics, whose structure is fundamentally determined by an electrical circuit analogy. Our general …

Human Chondrosarcoma Cells Acquire An Epithelial-Like Gene Expression Pattern Via An Epigenetic Switch: Evidence For Mesenchymal-Epithelial Transition During Sarcomagenesis., Matthew P. Fitzgerald, Francoise Gourronc, Melissa L.T. Teoh, Matthew J. Provenzano, Adam J. Case, James A. Martin, Frederick E. Domann

Journal Articles: Cellular & Integrative Physiology

Chondrocytes are mesenchymally derived cells that reportedly acquire some epithelial characteristics; however, whether this is a progression through a mesenchymal to epithelial transition (MET) during chondrosarcoma development is still a matter of investigation. We observed that chondrosarcoma cells acquired the expression of four epithelial markers, E-cadherin,desmocollin 3, maspin, and 14-3-3σ, all of which are governed epigenetically through cytosine methylation. Indeed, loss of cytosine methylation was tightly associated with acquired expression of both maspin and 14-3-3σ in chondrosarcomas. In contrast, chondrocyte cells were negative for maspin and 14-3-3σ and displayed nearly complete DNA methylation. Robust activation of these genes was also …

Rit Gtpase Signaling Mediates Oxidative Stress Resistance And Survival Of Adult Newborn Neurons After Traumatic Brain Injury, Weikang Cai

Theses and Dissertations--Molecular and Cellular Biochemistry

The small GTPases function as molecular switches to control diverse signaling cascades. The mammalian Rit and Rin, along with Drosophila Ric, comprise an evolutionarily conserved subfamily of the Ras-related GTPases. Previous studies using cultured cell models suggested that Rit was involved in the control of cell proliferation, transformation, neuronal differentiation, morphogenesis, and cell survival, but the principal physiological function of Rit remained uncharacterized.

To address this outstanding question, we employed a genetic approach, engineering a Rit knockout mouse. Using this animal model, we demonstrate a central role of Rit in governing cell survival in a p38-dependent fashion. Primary mouse embryonic …

Hiv-1 Clade B And C Isolates Exhibit Differential Replication: Relevance To Macrophage-Mediated Neurotoxicity, Agnes A. Constantino, Yunlong Huang, Hong Zhang, Charles Wood, Jialin C. Zheng

Nebraska Center for Virology: Faculty Publications

HIV-associated neurocognitive disorders (HAND) continue to be a consequence of HIV-1 infection among clade B-infected individuals. In contrast, the incidence of severe neurological impairment is lower among clade C-infected patients in regions of Sub-Saharan Africa and India. Biological aspects such as replication, cytopathicity, inflammatory response, and neurotoxicity unique to each clade influence neuropathogenicity and ultimately affect the clinical outcome of the disease. We hypothesize that productive infection by clade C isolates leads to macrophagemediated neurotoxicity, although to a lesser extent than clade B isolates. Using a panel of primary isolates of clades B and C we demonstrated that clade B …

The Zambia Children's Ks-Hhv8 Study: Rationale, Study Design, And Study Methods, Veenu Minhas, Kay L. Crabtree, Ann Chao, Janet M. Wojcicki, Adrian M. Sifuniso, Catherine Nkonde, Chipepo Kankasa, Charles D. Mitchell, Charles Wood

Nebraska Center for Virology: Faculty Publications

The epidemic of human immunodeficiency virus in Zambia has led to a dramatic rise in the incidence of human herpesvirus-8 (HHV-8)–associated Kaposi's sarcoma in both adults and children. However, there is a paucity of knowledge about the routes of HHV-8 transmission to young children. The Zambia Children's KS-HHV8 Study, a large, prospective cohort study in Lusaka, Zambia, was launched in 2004 to investigate the role of household members as a source of HHV-8 infection in young children and social behaviors that may modify the risk of HHV-8 acquisition. This cohort is distinct from other epidemiologic studies designed to investigate HHV-8 …

Consensus-Based Reporting Standards For Diagnostic Test Accuracy Studies For Paratuberculosis In Ruminants, Ian A. Gardner, Søren S. Nielsen, Richard J. Wittington, Michael T. Collins, Douwe Bakker, Beth Harris, Srinand Sreevatsan, Jason E. Lombard, Raymond Sweeney, David R. Smith, Jerrie Gavalchin, Shigetoshi Eda

School of Veterinary and Biomedical Sciences: Faculty Publications

The Standards for Reporting of Diagnostic Accuracy (STARD) statement was developed to encourage complete and transparent reporting of key elements of test accuracy studies in human medicine. The statement was motivated by widespread evidence of bias in test accuracy studies and the finding that incomplete or absent reporting of items in the STARD checklist was associated with overly optimistic estimates of test performance characteristics. Although STARD principles apply broadly, specific guidelines do not exist to account for unique considerations in livestock studies such as herd tests, potential use of experimental challenge studies, a more diverse group of testing purposes and …

Immunohistochemical Evaluation Of The Effects Of Nebivolol On Intimal Hyperplasia Following Endothelial Injury, İlker Akar, Ali̇ Rahman, M. Cengi̇z Çolak, Bi̇lal Üstündağ, İbrahi̇m Hani̇fi̇ Özercan, Ayhan Uysal

Turkish Journal of Medical Sciences

Intimal hyperplasia is a vascular remodeling process. It is a clinical problem that forms in the vascular wall as a result of smooth muscle cell migration, proliferation, and extracellular matrix accumulation. In this study we examined the immunohistochemical evaluation of the effects of nebivolol on intimal hyperplasia in damaged endothelial tissue. Materials and methods: The study was conducted using 21 rabbits equally divided into 3 groups: control, solvent, and nebivolol. The rabbits in the control group only underwent balloon injury of the abdominal aorta. The rabbits in the solvent group and nebivolol group underwent balloon injury and were treated with …

Assessment Of The Left Atrial Longitudinal Myocardial Function By Assessment Of The Left Atrial Longitudinal Myocardial Function By The Strain And Strain Rate Echocardiography In Patients With Rheumatic Mitral Stenosis*, Enbi̇ya Aksakal, Serdar Sevi̇mli̇, Hanefi̇ Yekta Gürlertop, Mehmet Ali̇ Elbey, Muhammed Hakan Taş, Fuat Gündoğdu, Mustafa Kemal Erol, Şule Karakelleoğlu

Turkish Journal of Medical Sciences

To evaluate the regional left atrial (LA) myocardial functions and time to peak deformations by the longitudinal strain (S) and strain rate (Sr) echocardiography in isolated mitral stenosis (MS) patients for 3 LA periods (contractile, reservoir, and conduit periods). Materials and methods: Included in the study were 30 MS patients and 30 healthy controls. Longitudinal peak S and Sr indices, time to peak S and time to peak Sr, and systolic and diastolic velocities were measured from the color Doppler myocardial imaging data, for each LA period. Results: For all 3 periods, all of the segment S values and most …

Role Of Calcium-Activated Potassium Channels In Glioblastoma Volume Regulation, Michael Bryan Mcferrin

All ETDs from UAB

The most common and most malignant gliomas are the Grade IV Glioblastoma Multiforme (GBM), characterized by a highly proliferative tumor mass and extremely invasive phenotype that allows for profuse dispersal of tumor cells throughout the brain. GBM cells must specifically regulate their cell volume to thrive within the edematous tumor mass and infiltrate throughout the tortuous extracellular spaces of the brain. These rapid and directed volume changes are governed by the controlled flux of potassium and chloride ions across the cell membrane, which move osmotically obliged water. The goal of this dissertation was to investigate the role of calcium-activated potassium …

Strategies For Combined Screening And Imaging Of Breast Cancer, Jason Morgan Warram

All ETDs from UAB

Successful treatment of breast cancer directly correlates with tumor stage and grade at diagnosis. Early diagnosis leads to a five-year relative survival rate of 96.8% as opposed to only a 22.5% five-year survival rate when diagnosed at late stage. Cancer-specific mechanisms need to be extended to enable cancer detection in an individual patient, in particular, the metastatic burden that currently cannot be assessed by conventional imaging. This approach for cancer detection would remove the biases of patient characteristics, permit immediate diagnostic feedback, improve sensitivity for early detection of small metastatic lesions, and be cost effective. Toward this goal, the cancer-specific …

Ecology And Transmission Of Eastern Equine Encephalitis Virus In The Southeastern United States, Gregory Scott White

All ETDs from UAB

The virus Eastern Equine Encephalitis virus (EEEV) is a highly pathogenic arthropod-borne virus (arbovirus) present in the US. The virus is listed as a reportable illness to the Centers of Disease Control and Prevention (CDC) and is also listed as a select agent by Human Health and Services (HHS). Studies on EEEV starting back in the 1930's have determined many important facets of the ecology, transmission and evolution of the virus. It is understood that in many endemic foci, the mosquito Culiseta melanura is the primary enzootic vector of the virus. EEEV is thus maintained in an enzootic cycle between …

In Vivo Analysis Of The Natural Diversity Of The Igr Ires Family And Characterization Of The Role Of Ribosomal Protein S25 In Ires-Mediated Translation, Marla Ilene Hertz

All ETDs from UAB

Translation of the majority of eukaryotic mRNAs is initiated upon recognition of its 5' cap structure by translation initiation factors in so-called cap-dependent translation. Cap-dependent translation is repressed during cell stress and translation initiation by internal ribosome entry sites (IRESs) predominates. IRESs, located in the 5' untranslated region of specific mRNAs, recruit the ribosome independent of the 5' cap and are essential regulatory elements in many RNA viruses and cellular messages. The dysregulation of cellular IRESs has been linked to cancer because they regulate the expression of genes involved in growth, development and stress response. In comparison to cap-dependent translation, …

Qualitative Analysis Of Hiv-1-Specific Cd8 T Cell Responses, Olusimidele Tolulope Akinsiku

All ETDs from UAB

In the absence of antiretroviral therapy (ART), the majority of individuals infected with human immunodeficiency virus-1 (HIV-1) will develop AIDS. HIV-1-infected controllers are exceptions to the rule; without the use of ART, these individuals spontaneously control virus replication. A better understanding of the immune mechanisms that mediate delayed disease progression, as seen in controllers, will provide valuable insight to the design and development of an effective HIV-1 vaccine. CD8 T cells are important mediators of the antiviral immune response. However, it is unclear which components of the response are critical for long-lasting protection during HIV-1 infection. We first review methods …

The Role Of Protease-Activated Receptor-1 In Synaptic Plasticity And Memory, Antoine Gabriel Almonte

All ETDs from UAB

Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. While previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. In the central nervous system (CNS), PAR1 is expressed in glial cells in the hippocampus, a brain region critical for memory formation. I am particularly interested in PAR1 because its activation enhances the function of N-methyl-D-aspartate receptors (NMDARs), which are required for some forms of behavioral learning and synaptic plasticity. …

Structural And Functional Studies On Group A Streptococcal Bacteriophage Hyaluronidase, Joo Hyoung Lee

All ETDs from UAB

Aberrant hyaluronan production is frequently associated with tumors where the elevated levels of tumoral hyaluronan are often associated with higher expression levels of cellular hyaluronidases that produce saturated hyaluronan fragments with divergent pro-tumoral activities. In this thesis, we provide evidence that different hyaluronan metabolism of bacteriophage hyaluronidase (HylP) elicits distinct alteration in breast cancer cell behavior. We demonstrate through comparative analysis with bovine testicular hyaluronidase (BTH) that higher enzyme activity, specificity for hyaluronan and production of unsaturated oligosaccharides render HylP to have profound effects on growth, migration and invasion activities of breast carcinoma cells, whereas BTH and its saturated metabolites …

Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu

All ETDs from UAB

Changes in the glioma microenvironment including oxygen (O2) levels, supply of amino acid such as L-glutamate and L-cystine and glutathione (GSH) concentrations play a critical role in glioma biology. Previous data from our laboratory and others have implicated the L-cystine/L-glutamate exchanger, system xc- in the invasion and proliferation of cancers including glioma. The central aim of this dissertation was to characterize the contribution of L-cystine uptake, GSH synthesis and L-glutamate release to migration and proliferation of glioma cells. In my first study, I examined the role of system xc- mediated L-glutamate release on glioma migration. I show that activation of …

In Vivo Interactions Between Virus Genomes And Host Proteins For Members Of The Order Picornavirales, Erik Michael Lenarcic

All ETDs from UAB

A significant number of pathogens of economical and medical importance are positive sense RNA viruses. Their genomes enter host cells and subvert them to support virus growth. These large-scale changes involve the co-opting of cellular proteins through interactions with viral RNA and proteins. Characterizing these interactions leads to a better understanding of viral life cycles and the identification of new antiviral therapies. The order Picornavirales contains viruses that infect a wide array of eukaryotes. Their genomes serve as a messenger RNA (mRNA) that is translated by host ribosomes cap-independently through an internal ribosome entry site (IRES). Most members of the …

The Intestinal Extracellular Matix As An Innate Regulator Of Effector T-Cell Responses, Kayci Renee Huff

All ETDs from UAB

Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. Here we uncovered a role for intestinal stromal products in the innate regulation of effector T-cells. Stroma-conditioned media (S-CM) derived from normal human intestinal stroma (TGF-&betahi/IL-6lo/IL-1ßlo) significantly down-regulated T-cell proliferation and IFN-&gamma production compared to S-CM derived from inflamed Crohn's mucosa (TGF-&betahi/IL-6hi/IL-1&betahi). Antibody neutralization studies showed that TGF-&beta in normal S-CM inhibited T-cell proliferation and IFN-&gamma production, whereas IL-6 plus IL-1&beta in Crohn's S-CM promoted T-cell proliferation, and the IL-1&beta alone promoted IFN-γ and IL-17 release. Importantly, stromal cells in normal tissue produce TGF-&beta and contribute to mucosal homeostasis …

Role Of Membrane Lipids In Modulating Protein Structure & Function, Ray Supriyo

Electronic Theses and Dissertations

A-B family of toxins consists of plant toxins such as ricin and bacterial toxins such as cholera. The A subunit is the enzymatic domain and the B subunit is the receptor binding domain. Commonly, these toxins bind to the target cell plasma membrane receptors through their B subunit followed by endocytosis and a transport to the endoplasmic reticulum (ER). Inside the ER, the A subunit dissociates from the rest of the toxin, unfolds and triggers the ER quality control mechanism of ER-associated degradation (ERAD). Most ERAD substrates are purged out of the ER into the cytosol for proteasomal degradation. However, …

Hybrid Adult Neuron Culture Systems For Use In Pharmacological Testing, Darin Keay Edwards

Electronic Theses and Dissertations

Neuronal culture systems have many applications, such as basic research into neuronal structure, function, and connectivity as well as research into diseases, conditions, and injuries affecting the brain and its components. In vitro dissociated neuronal systems have typically been derived from embryonic brain tissue, most commonly from the hippocampus of E18 rats. This practice has been motivated by difficulties in supporting regeneration, functional recovery and long-term survival of adult neurons in vitro. The overall focus of this dissertation research was to develop a dissociated neuronal culture system from human and animal adult brain tissue, one more functionally and developmentally correlative …

Genetic And Physiological Contribution Of Adrenergic Cells In Heart Development, Kingsley Osuala

Electronic Theses and Dissertations

The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are essential for cardiovascular development as embryos lacking NE/EPI begin to die abruptly between embryonic days 10.5 and 11.5 due to apparent cardiac failure. The objective of this research aims to elucidate the mechanism of the embryonic fatality observed in the NE/EPI deficient mouse model. Here we utilized the dopamine β- hydroxylase knockout (Dbh-/-) mouse model, which lacks the gene and subsequent enzyme necessary for the conversion of dopamine to norepinephrine. Embryonic mouse hearts were extracted from Dbh+/+ (control) and Dbh-/- (experimental model) mice for mRNA transcript expression profiling. These studies were …

Genetically Modified Es Cells Enhance Cardiac Repair And Regeneration In The Infarcted Heart, Carley E. Glass

Electronic Theses and Dissertations

Transplanted embryonic stem (ES) cells following myocardial infarction (MI) contribute to limited cardiac repair and regeneration with improved function. Therefore novel strategies are still needed to enhance the efficacy by which ES cells differentiate into cardiac cell types and inhibit adverse remodeling in the infarcted myocardium. Our studies evaluate whether genetic manipulation of transplanted ES cells employing miR- 1, a pro-cardiac microRNA, and TIMP-1, an anti-apoptotic and anti-fibrotic protein, will enhance cardiac myocyte differentiation, inhibit native cardiac apoptosis, and reduce fibrosis in the infarcted myocardium. Furthermore, we assess levels of associated pro- (caspase-3, PTEN) and anti-(Akt) apoptotic proteins as well …

Translocation Of The Cholera Toxin A1 Subunit From The Endoplasmic Reticulum To The Cytosol, Michael Prentice Taylor

Electronic Theses and Dissertations

AB-type protein toxins such as cholera toxin (CT) consist of a catalytic A subunit and a cell-binding B subunit. CT proceeds through the secretory pathway in reverse, termed retrograde trafficking, and is delivered to the endoplasmic reticulum (ER). In order for the catalytic A1 subunit to become active it must separate from the rest of the holotoxin, and this dissociation event occurs in the ER lumen. CTA1 assumes an unfolded conformation upon dissociation from the holotoxin and is recognized by ERassociated degradation (ERAD), a quality control system that recognizes and exports misfolded proteins to the cytosol for degradation by the …

Glial Differentiation Of Human Umbilical Stem Cells In 2d And 3d Environments, Hedvika Davis

Electronic Theses and Dissertations

During differentiation stem cells are exposed to a range of microenvironmental chemical and physical cues. In this study, human multipotent progenitor cells (hMLPCs) were differentiated from umbilical cord into oligodendrocytes and astrocytes. Chemical cues were represented by a novel defined differentiation medium containing the neurotransmitter norepinephrine (NE). In traditional 2 dimensional (2D) conditions, the hMLPCs differentiated into oligodendrocyte precursors, but did not progress further. However, in a constructed 3 dimensional (3D) environment, the hMLPCs differentiated into committed oligodendrocytes that expressed MBP. When co-cultured with rat embryonic hippocampal neurons (EHNs), hMLPCs developed in astrocytes or oligodendrocytes, based on presence of growth …

Role Of The Cardiomyocyte Circadian Clock In Modulating Myocardial Physiology And Pathophysiology, David Joseph Durgan

All ETDs from UAB

It is well established that multiple parameters of cardiovascular physiology and pathophysiology exhibit diurnal variations. For example, human heart rate and blood pressure peak during the morning and trough in the evening. Similarly, there is a morning prevalence for the onset of multiple adverse cardiovascular events, including myocardial ischemia, arrhythmias, and sudden cardiac death. Traditionally these rhythms have been attributed to rhythms in neurohumoral stimulation. However recent identification of the circadian clock mechanism in cardiovascular relevant cell types, including the cardiomyocyte, has prompted investigation into its role in modulating myocardial physiology and pathophysiology over the course of the day. Preliminary …

Intracellular Distribution Of Glycogen Synthase Kinase-3beta In The Brain, Johanna C. Gandy

All ETDs from UAB

The widely distributed serine/threonine kinase glycogen synthase kinase 3beta is well known for its multiple functions in the health brain tissue, which include cell fate, neuronal growth and remodeling, synaptic plasticity, and neuroinflammation. However much of GSK3beta focuses on its abnormal functions in neurological disorders like Alzheimer's Disease and psychiatric disorders. To maintain normal GSK3beta function in the brain, this constitutively active kinase must be strictly regulated. Many factors within the cell work together to influence GSK3beta activity. Two ways to regulate GSK3beta activity are through phosphorylation by upstream kinases or the formation of protein complexes that block substrate binding. …

Differential Contributions Of C-Kit Activating Mutations To Promotion Of Aml1-Eto Associated Neoplasia, Heidi Jean Nick

All ETDs from UAB

The t(8;21) translocation, which generates an AML1-ETO fusion protein (also known as RUNX1-ETO), is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Murine studies have demonstrated that AML1-ETO promotes the accumulation of myeloid progenitor cells with self-renewal capability and impaired differentiation capacity. However, AML1-ETO+ mice do not progress to AML in the absence of additional mutations, suggesting that expression of the translocation is insufficient for leukemogenesis. This hypothesis is supported by studies demonstrating the persistence of AML1-ETO-expressing hematopoietic progenitors obtained from patients in long-term clinical remission. Mutations affecting receptor tyrosine kinases, particularly c-KIT, are commonly detected …

Low And High Let Irradiation Of Human Aortic Endothelial Cells Induces Dose And Time Dependent Adhesion Of Monocytes Which Is Mediated By Chemokines Expressed By The Irradiated Endothelium., Saman Fatima Khaled

All ETDs from UAB

Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Since radiation also induces inflammation, a possible mechanism is a change in the adhesiveness of vascular endothelial cells, triggering pro-atherogenic accumulation of leukocytes. To investigate this mechanism at the cellular level, the effect of xrays, iron (Fe56) ions, and protons on adhesiveness of cultured human aortic endothelial cells (HAECs) was determined. HAECs were grown as monolayers and exposed to 0 to 30 Gy X-rays, 0, 2, and 5 Gy Fe56 ions, and 0, 0.5, and 2 Gy protons followed by measurement of …